Non-clinical evaluation of ventricular repolarization (ICH S7B): results of an interim survey of international pharmaceutical companies.

Introduction: The propensity of drugs to cause a potentially fatal arrhythmia, torsades des pointes (TdP), is a significant public health issue. The draft International Conference on Harmonization (ICH) S7B guidelines describe a battery of non-clinical studies to evaluate a drug's potential to prolong ventricular repolarization (VR); an accepted surrogate/risk factor for TdP. A worldwide survey of pharmaceutical industry practices, related to ICH S7B was conducted. The findings were presented at the 4th Annual Meeting of the Safety Pharmacology Society (SPS) meeting (Cincinnati, OH, Sept., 2004).

Methods: The survey was distributed by the SPS to 119 pharmaceutical companies; 29 surveys were returned. Survey topics included: (a) General Strategy and Testing for Risk of QT prolongation, (b) Study Timing and Relationship to Development, and (c) Application of GLPs.

Results: Respondents indicate that the basis for assessing prolongation of VR was to: remove compounds with an arrhythmic risk to humans (86%), to satisfy regulatory expectations (79%), or to avoid obstacles in the clinical development of a compound (86%). Development of a compound based on prolongation of VR was halted for 52% of respondents (compared to 45% in a 2003 survey). Models used to evaluate changes in VR included: human ether a go-go related gene (hERG) (93%), action potential duration (APD) (68%; compared to 80% in the 2003 survey), and in vivo QT (100%). The distribution of assays being requested by regulatory agencies includes the hERG (83%), APD (28%), and in vivo QT (79%). In spite of uncertainty regarding the final requirements of ICH S7B, organizations continue to implement (36%) and validate (60%) their electrophysiology laboratories.

Summary: The survey results indicate that pharmaceutical companies are testing for VR prolongation of drug candidates and that institutions have established in-house or outsourced capabilities to evaluate this potential risk, even in the absence of final guidelines.